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Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease

Abstract:Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD).
Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed.
Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained
relatively constant across Braak PD stages in ILBD.
Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.

Neurology. 2012 Dec 11;79(24):2307-14. doi: 10.1212. PMID: 23152586

Modeling regional vulnerability to Alzheimer pathology

Royall DR, Palmer RF, Petrovitch H, Ross GW, Masaki K, White LR

Abstract:Latent growth curve (LGC) models estimate change over time in a cohort's serially obtained measurements. We have applied LGC techniques to a spatial distribution of Alzheimer's disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study. Neurofibrillary tangle (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. The gradient of spatial change in neuritic plaque (dNP), was significantly associated with that of neurofibrillary tangle (dNFT), but weakly and inversely (r = -0.12; p < 0.001). Both dNFT and dNP correlated significantly and inversely with Braak stage. Sixty-one percent of the variance in Braak stage was explained by dNFT independent of covariates. Only dNFT was significantly associated with longitudinal change in cognition. Only dNP was associated with apolipoprotein (APOE) e4 burden. This is the first application of LGC models to spatially-ordered data. The result is a quantification of the interindividual variation in the interregional vulnerability to Alzheimer's disease lesions.

Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort

Rantanen T, Masaki K, He Q, Ross GW, Willcox BJ, White L

Abstract:We studied prospectively the midlife handgrip strength, living habits, and parents' longevity as predictors of length of life up to becoming a centenarian. The participants were 2,239 men from the Honolulu Heart Program/Honolulu-Asia Aging Study who were born before the end of June 1909 and who took part in baseline physical assessment in 1965-1968, when they were 56-68 years old. Deaths were followed until the end of June 2009 for 44 years with complete ascertainment. Longevity was categorized as centenarian (≥100 years, n = 47), nonagenarian (90-99 years, n = 545), octogenarian (80-89 years, n = 847), and ≤79 years (n = 801, reference). The average survival after baseline was 20.8 years (SD = 9.62). Compared with people who died at the age of ≤79 years, centenarians belonged 2.5 times (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23-5.10) more often to the highest third of grip strength in midlife, were never smokers (OR = 5.75 95% CI = 3.06-10.80), had participated in physical activity outside work (OR = 1.13 per daily hour, 95% CI = 1.02-1.25), and had a long-lived mother (≥80 vs. ≤60 years, OR = 2.3, 95% CI = 1.06-5.01). Associations for nonagenarians and octogenarians were parallel, but weaker. Multivariate modeling showed that mother's longevity and offspring's grip strength operated through the same or overlapping pathway to longevity. High midlife grip strength and long-lived mother may indicate resilience to aging, which, combined with healthy lifestyle, increases the probability of extreme longevity.

Abstract:An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.

Ankle-to-brachial index and dementia: The Honolulu-Asia Aging Study

Laurin D, Masaki KH, White LR, Launer LJ

Abstract:BACKGROUND:
Measurement of the ankle-to-brachial index (ABI) is a noninvasive test to assess peripheral arterial disease. A low ABI is a strong correlate of cardiovascular disease and subsequent mortality. Evidence indicates the existence of vascular components in the pathogenesis of dementia. Here, we examine the association of ABI with dementia and subtypes.
METHODS AND RESULTS:
Data are from the Honolulu-Asia Aging Study (HAAS), a prospective community-based study of 3734 Japanese American men 71 to 93 years of age at baseline in 1991 to 1993. The analysis included 2588 men who were free of dementia at the first assessment, had an ABI measure, and were examined up to 2 more times for dementia between 1994 and 1999. The sample included 240 incident cases of dementia (144 of Alzheimer's disease, 46 of vascular dementia, and 50 of dementia of other causes). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from Cox proportional-hazards models with age as the time scale after adjustment for education, year of birth, high blood pressure, body mass index, diabetes mellitus, cholesterol concentration, smoking status, alcohol consumption, and apolipoprotein E epsilon4 allele. A low ABI was associated with an increased risk of dementia and vascular dementia (HR, 1.66; 95% CI, 1.16 to 2.37; and HR, 2.25; 95% CI, 1.07 to 4.73, respectively). ABI was weakly associated with Alzheimer's disease (HR, 1.57; 95% CI, 0.98 to 2.53), particularly in the apolipoprotein E epsilon4 carriers (HR, 1.43; 95% CI, 1.02 to 1.96).
CONCLUSIONS:
These results suggest that ABI, a measure of atherosclerosis, is associated with the incidence of total dementia, vascular dementia, and Alzheimer's disease in carriers of the apolipoprotein E epsilon4 allele.